Jack Elias (left) and Geoffrey Chupp have discovered a protein that regulates the immune response, and hence the severity of inflammation and cell damage, in asthma and other conditions. (Photo by
Terry Dagradi)

Asthma: from mouse to man and back again

Bench-to-bedside approach yields important insights into a common disorder

It all started with a mouse, says Jack A. Elias, M.D., chair of the Department of Internal Medicine and an expert on lung diseases. A few years ago, Elias, the Waldemar Von Zedtwitz Professor of Medicine, discovered that mice he had engineered to develop asthma had high levels of a very unusual enzyme. The enzyme, chitinase, is more commonly found in plants and lower organisms, where it breaks down chitin (pronounced “ky-tin”), an abundant and sturdy sugar polymer that gives insect and crustacean shells their resilience and strength. In humans, chitinases are thought to provide a first line of defense against fungi and some parasitic worms that also bear outer coats containing chitin.

That result was intriguing, because environmental exposure to indoor pollutants such as fungi and dust mites has been blamed for the growing incidence of asthma over the last decades. Translating the chitinase finding quickly from mice into humans, Elias and Geoffrey L. Chupp, M.D., associate professor of medicine and director of the Yale Center for Asthma and Airway Disease (YCAAD) soon discovered that people with severe asthma have high levels of a chitinase-related protein, YKL-40, in their blood. Then, they found that YKL-40 plays a central role in regulating the immune response and driving the lung inflammation that is at the root of asthma. The work could lead to new methods for diagnosing and treating asthma, a disease that affects an estimated 20 million Americans, including 9 million children.

In the mouse experiments, YKL-40 was not the original protein of interest for Elias. It is not a true chitinase; YKL-40 can bind to chitin, but it lacks the enzymatic activity required to break down the tough polymer. However, as reported in The New England Journal of Medicine in 2007, YKL-40 was known to circulate in the blood, and it could be measured with a simple test. “We saw this chitinase relative and thought ‘the cousin may actually be prettier than the girl we’d been dating,’ ” Elias said, describing the investigators’ early attraction to YKL-40 as a potential blood marker of asthma.

Enter Chupp, a skilled researcher whom Elias had recruited to Yale in 1997. Chupp had taken on the challenge of building up a clinical research program on lung diseases to parallel the basic research effort Elias had organized at the medical school.

The result was YCAAD, an active clinic that draws referrals from all over Connecticut and surrounding states. Besides receiving the best available treatment, Chupp says, all the patients at YCAAD get the opportunity to contribute to research. So far, he has enrolled more than 500 subjects into a well-characterized cohort of asthma sufferers, many of whom have a severe form of the disease.

Because of the presence of YCAAD, when YKL-40 popped up in the mouse studies, Chupp had everything ready to go to apply the findings to human disease. After measuring YKL-40 levels in blood samples from 200 patients, the researchers found that the protein was elevated in people with asthma, and its levels were highest in those with severe disease. The same held true in two other patient groups they tested, from Wisconsin and Paris. Levels of YKL-40 in the blood and lungs of these patients correlated with the use of medication to control asthma, with how often people were hospitalized and with the appearance of irreversible lung damage. For the first time, the severity of airway scarring could be measured by looking at a blood sample.

The next question was whether high levels of YKL-40 caused asthma symptoms or merely signaled the damage wrought by the disease. To find out, Chupp looked for differences in the genetic makeup of people with high or low YKL-40. The results, reported earlier this year, also in The New England Journal of Medicine, show that people who have a particular version of the YKL-40 gene tend to have a higher blood level of YKL-40, and along with that, a greater risk of getting asthma.

Those results were suggestive, but still did not prove that YKL-40 caused any of the pathological changes of asthma. To settle that question, Elias and Chupp went back to mice, genetically engineering them to have either none of the mouse equivalent of YKL-40, or too much. The result, they say, was clear. Animals lacking the protein were resistant to developing the type of inflammation that causes asthma, while animals with extra protein had an overactive immune response and more severe disease.

Further work revealed that YKL-40 is part a novel regulatory pathway governing the level of inflammation in asthma and in other conditions. The protein works by slowing the rate at which activated immune cells die off.

“We believe YKL-40 is a kind of a rheostat that sets the level of inflammation,” Elias explains. “If you’re a normal healthy person with a normal to low level of the stuff, when you have inflammation, it clears normally, but if you’re a person with high levels of YKL-40, you end up with a more robust and chronic response and the consequences are therefore worse.”

The latest findings suggest that not only is the protein a potential disease reporter, but also a likely target for new therapies. The YKL-40 story is a perfect model of how the interplay of animal and human research can speed basic discoveries to the clinic, Elias says. The work proceeded so rapidly because Yale’s group of asthma experts functions as an integrated unit. “We have master clinicians on one side and master scientists on the other side and the two constantly interact with each other,” he explains. “We believe that you have to bounce back and forth to move things forward.”

A Simple Blood Test Might Identify Most Severe Asthma

Dr. Geoffrey Chupp, associate professor of medicine, talks about his discovery that a certain protein might prove to be a good biomarker to identify the worst cases of asthma.